The long-term goal of this study is to understand the emergence of pandemic strains of influenza virus at the molecular level. New viral hemagglutinin (HA) and/or neuraminidase (NA) genes that entered the human viral gene pool in 1957 and 1968 were associated with a substantial number of influenza deaths. Moreover, epidemiologic studies on the 1918-1919 influenza pandemic suggest that generation of catastrophic pandemic viruses may involve the acquisition of enhanced virulence during replication in humans. A recent episode of human infection by an HSN1 avian influenza virus in Hong Kong underscores the possibility that avian virus can be transmitted directly to humans during the emergence of a pandemic strain. Although well-described in birds, molecular mechanisms that would account for the increased pathogenicity of influenza viruses in human hosts are lacking. Thus, the current research proposal seeks (1) to establish the phylogenetic relationships of the recently isolated HSN1 Hong Kong influenza virus and identify the properties (e.g., receptor specificity and HA cleavability) that might account for its replication and pathogenicity in humans, (2) to elucidate the role of HA-NA interplay in influenza virus replication in a new host, and (3) to identify the NA and HA structural changes that contribute to plasminogen-mediated HA cleavage, leading to enhanced virulence of influenza viruses. Over the past three decades, a number of several new viral pathogens have appeared in humans (including human immunodeficiency virus, influenza A virus, Hanta virus, Ebola virus, monkeypox virus, and Borna virus), after being maintained in small isolated human populations or in other animal hosts. Understanding the mechanism(s) by which these viruses emerge is essential for predicting the likelihood of a new pandemic and for developing effective counter-measures. Influenza A viruses provide an unparalled model of a pathogen that rapidly mutates to a form capable of global devastation. Studies addressing the specific aims will further understanding of the processes that give rise to global outbreaks of viral disease and, therefore, may stimulate efforts to devise preventative strategies.